Abstract

Background

Atherosclerosis is an inflammatory process of the arterial walls and is initiated
by endothelial dysfunction accompanied by an imbalance in the production of reactive
oxygen species (ROS) and nitric oxide (NO). Sildenafil, a selective phosphodiesterase-5
(PDE5) inhibitor used for erectile dysfunction, exerts its cardiovascular effects
by enhancing the effects of NO. The aim of this study was to investigate the influence
of sildenafil on endothelial function and atherosclerosis progression in apolipoprotein
E knockout (apoE−/−) mice.

Methods

ApoE−/− mice treated with sildenafil (Viagra®, 40 mg/kg/day, for 3 weeks, by oral gavage)
were compared to the untreated apoE−/− and the wild-type (WT) mice.

Aortic rings were used to evaluate the relaxation responses to acetylcholine (ACh)
in all of the groups. In a separate set of experiments, the roles of NO and ROS in
the relaxation response to ACh were evaluated by incubating the aortic rings with
L-NAME (NO synthase inhibitor) or apocynin (NADPH oxidase inhibitor). In addition,
the atherosclerotic lesions were quantified and superoxide production was assessed.

Results

Sildenafil restored the vasodilator response to acetylcholine (ACh) in the aortic
rings of the apoE−/− mice. Treatment with L-NAME abolished the vasodilator responses to ACh in all three
groups of mice and revealed an augmented participation of NO in the endothelium-dependent
vasodilation in the sildenafil-treated animals. The normalized endothelial function
in sildenafil-treated apoE−/− mice was unaffected by apocynin highlighting the low levels of ROS production in
these animals. Moreover, morphological analysis showed that sildenafil treatment caused
approximately a 40% decrease in plaque deposition in the aorta.

Conclusion

This is the first study demonstrating the beneficial effects of chronic treatment
with sildenafil on endothelial dysfunction and atherosclerosis in a model of spontaneous
hypercholesterolemia. These data indicate that the main mechanism of the beneficial
effect of sildenafil on the endothelial function appears to involve an enhancement
of the NO pathway along with a reduction in oxidative stress.